FNT continues since July Again, for most patients FNT was used as a local boost following external photon therapy. A median total dose of 6 Gy max 12 Gy, min 1. For head-and-neck cancer patients thermoplastic mask systems were used and Computer tomography CT imaging acquired in treatment position was used to define the target volume and optimal beam positioning.
For superficial skin lesion, the target volumes were determined clinically and light fields were used to define the optimal treatment position and MLC shape. Figure 3. Thirty seven patients with superficial skin lesions were evaluated for tumor response and the effect of FNT on their quality of life QoL was also evaluated. A median total dose of 6 Gy range 2—12 Gy was applied at a median single dose of 2 Gy. Mean treatment field size was All patients were treated in accordance with the principles of the Declaration of Helsinki.
The scientific use of retrospective data has been explicitly allowed by Bavarian federal law BayKrG Art 27 4. Additionally, all patients gave their written informed consent and agreed that their scientific data could be used. Due to the manifold treatment indications that were treated with FNT between and , we focused on subgroup of patients for data presentation in the present manuscript in order to deliver data comparable to with other treatment possibilities.
Therefore groups of patients were pooled according to the entity treated and the technique used and analyzed separately with special focus on LC, OS, and toxicity. Because of the relatively low numbers of patients treated with FNT compared to conventional photon therapy and due to the individual character of FNT treatments, a thorough patient follow up was enforced. Patients were regularly seen in a dedicated outpatient department and if patients did not show up for their appointment, their general practitioners were contacted for follow up and toxicity information.
Patient data was analyzed at a median follow up time of 8 years range 2—17 years. Eighty percent of the patients were still alive after 5 years. Patient data were analyzed at a median follow up time of 23 months range 4—65 months. Although FNT has been around since the s, the number of publications on this topic is limited and unlike in most fields of oncology, the number of publications per year has not increased, but even decreased over the last decades see Figure 5.
This is explained by the clinical difficulties that developed during the application of FNT: In spite of benefits based on the biological properties of neutrons, the rates of treatment-induced side effects limited the widespread use of neutron therapy, and thus almost removed neutron centers from clinical radiation oncology 9 , 26 , For certain indications, however, few centers are still in operation, including also approaches with BNCT 28 — Figure 5.
Gold nanoparticles as a potent radiosensitizer in neutron therapy
Due to the distinct physical features of neutrons, radiation protection remains challenging and high precision modern radiotherapy, as it can be delivered by a modern linear accelerator with photons, requires tremendous efforts in terms of costs and infrastructure to realize. Horrible side effects, which were caused in the early days of FNT when the new technique was enthusiastically embraced and the knowledge on dosing and treatment planning was not yet existent, sank deep into the collective memory 31 — Also the clinical use of a fixed neutron RBE was bound to cause problems, despite good radiobiological data which showed its variability.
Therefore it seems like the radiation community is about to draw the veil of oblivion over FNT. And this is also true for tumor entities that are known to be resistant to conventional radiation treatment. However, even if LC can be achieved, this often does not lead to a favorable OS, since survival is often limited by early distant metastases, as it was just recently shown by Liao et al.
Therefore in most treatment indications, FNT is considered useful today, and OS might not be the appropriate tool to measure the treatment success. We saw some tremendous improvement in QoL for individual patients due to tumor regression and reduced effort in wound care. Most of the patients treated with FNT stated that they had profited from this treatment and that their personal situation was improved after FNT.
The main reason for this is, as stated above, in our opinion the good tumor response.
Since most lesions treated were superficial, the treatment success was also easily comprehensible to the patient. So it can be stated that for superficial metastases, FNT offers a well-tolerated and effective treatment option. The high RBE also leads to short treatment times and few treatment sessions, which adds to the attractiveness in terms of a palliative treatment option. The experience made with FNT should be evaluated carefully since it might be useful not only to learn more about FNT itself, but also about high-LET particle therapy in general.
Since neutron therapy has been around since the s, there are long-term survivors that can help to identify risk and chances associated with heavy-particle therapy. It has to be mentioned in this regard that there is a potentially increased risk of secondary malignancies caused by neutron irradiation, especially to healthy tissues outside of the treatment field. Large concerted efforts such as the Euratom Allegro project are currently carried out to further evaluate this topic In the treatment of patients with ACC of the salivary gland, we saw some patients with osteonecrosis of the mandibular bone.
Of course the relative numbers of those complications are considerably high compared to the numbers we are accepting in the photon community. But it also has to be considered that some of these patients had large tumors that were already infiltrating the bone, so the reason for the osteonecrosis is not necessarily the treatment but the tumor itself. But still, this is also a warning that high LET-radiation and comparatively high single doses might not be appropriate in sensitive areas, especially when the tools to determine the anatomical dose application are limited.
Another point, why it might be too early to forget about FNT, is the recent developments in cancer immunotherapy. In , immunotherapy was elected as the breakthrough of the year Now, even in some patients with metastasized melanoma, long-term survivors can be found The combination of radiotherapy and immunotherapy seems to be a fruitful collaboration.
Since immunotherapy is able to offer improved OS but often fails to achieve LC in progressive tumor lesions, local radiotherapy might prove to be an ideal combination. Not only can radiotherapy lead to LC within the treatment field, it can even cause tumor regression outside of the treatment field, the so called abscopal effects So far neither the optimal time point to combine the modalities nor the optimal dosing schedule is known.
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But there is reason to believe if the radiotherapy would cause a greater immune-stimulatory effect, than the collaboration between the two treatment partners would be even more effective. Since FNT is usually applied only once or twice per week, lymphocyte depletion within the treatment field, as it is caused by daily routine radiotherapy, might be less pronounced. Thus, especially in patients were immunotherapy is appropriate, such as malignant melanoma, combination with FNT for skin lesions could be a promising alternative.
Fast neutron therapy using reactor generated fission neutrons is limited due to the relatively low penetration depth of the beam. Therefore, in most cases, therapy is limited to superficial lesions as they often occur in recurrent breast cancer at the thoracic wall or in recurrent malignant melanoma skin lesions. To measure the treatment success in these palliative concepts, determination of the OS or progression free survival might not be an appropriate tool. Some clinically meaningful improvements in terms of local tumor regression with relatively low side effects were observed, leading to improved QoL and a reduced effort for wound management for the individual patients.
Patients treated with FNT should be treated within clinical study protocols and the remaining neutron facilities should share their experiences, as it is done for other hadron therapies as well As there is a growing interest in high-LET therapy with a growing number of hadron therapy centers around the globe, the clinical data generated by neutron therapy might help to develop biologically driven treatment planning algorithms.
Also recent advances in immunotherapy call to reevaluate the benefit of neutron therapy, where good local tumor control can be achieved within short treatment times and immune-modulatory effects might be more pronounced compared to conventional irradiation. Drafting of manuscript: HS. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The merits of cell kinetic parameters for the assessment of intrinsic cellular radiosensitivity to photon and high linear energy transfer neutron irradiation.
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